Premium
Signal transduction by transforming growth factor‐β: A cooperative paradigm with extensive negative regulation
Author(s) -
Engel Michael E.,
Datta Pran K.,
Moses Harold L.
Publication year - 1998
Publication title -
journal of cellular biochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.028
H-Index - 165
eISSN - 1097-4644
pISSN - 0730-2312
DOI - 10.1002/(sici)1097-4644(1998)72:30/31+<111::aid-jcb15>3.0.co;2-5
Subject(s) - r smad , signal transduction , smad , microbiology and biotechnology , biology , transforming growth factor beta , tgf beta signaling pathway , smad2 protein , phosphorylation , tgf beta receptor 2 , transforming growth factor , endoglin , stem cell , cd34
Transforming growth factor‐β (TGF‐β) represents an evolutionarily conserved family of secreted factors that mobilize a complex signaling network to control cell fate by regulating proliferation, differentiation, motility, adhesion, and apoptosis. TGF‐β promotes the assembly of a cell surface receptor complex composed of type I (TβRI) and type II (TβRII) receptor serine/threonine kinases. In response to TGF‐β binding, TβRII recruits and activates TβRI through phosphorylation of the regulatory GS‐domain. Activated TβRI then initiates cytoplasmic signaling pathways to produce cellular responses. SMAD proteins together constitute a unique signaling pathway with key roles in signal transduction by TGF‐β and related factors. Pathway‐restricted SMADs are phosphorylated and activated by type I receptors in response to stimulation by ligand. Once activated, pathway‐restricted SMADs oligomerize with the common‐mediator Smad4 and subsequently translocate to the nucleus. Genetic analysis in Drosophila melanogaster and Caenorhabditis elegans , as well as TβRII and SMAD mutations in human tumors, emphasizes their importance in TGF‐β signaling. Mounting evidence indicates that SMADs cooperate with ubiquitous cytoplasmic signaling cascades and nuclear factors to produce the full spectrum of TGF‐β responses. Operating independently, these ubiquitous elements may influence the nature of cellular responses to TGF‐β. Additionally, a variety of regulatory schemes contribute temporal and/or spatial restriction to TGF‐β responses. This report reviews our current understanding of TGF‐β signal transduction and considers the importance of a cooperative signaling paradigm to TGF‐β‐mediated biological responses. J. Cell. Biochem. Suppls. 30/31:111–122, 1998. © 1998 Wiley‐Liss, Inc.